The myelin sheath is rich in lipids (70%) and proteins (30%), including myelin basic protein (MBP) and proteolipid protein (PLP). These molecules are synthesized by OLs and assembled into tightly compacted lamellar structures (Franklin and Ffrench-Constant, 2008). As a lipid-rich membrane wrapping around nerve fibers, the myelin sheath serves as a critical insulating structure for neuronal axons. Its insulating properties enable saltatory conduction of action potentials between Nodes of Ranvier (Franklin and Ffrench-Constant, 2008; Hartline and Colman, 2007), significantly increasing conduction velocity while reducing energy expenditure and protecting the axons. In addition to supporting fundamental neural processes by enhancing signal velocity, myelin is also pivotal in higher-order cognitive functions, such as learning, memory, and executive control. The lipid bilayer structure of myelin serves to electrically insulate axons from adjacent tissues, thereby preventing signal leakage or cross-talk during impulse conduction and ensuring the fidelity of action potentials. Myelin significantly enhances the velocity of nerve impulse conduction through saltatory conduction (Boda, 2021), a process in which action potentials propagate by leaping between the Nodes of Ranvier. This mechanism eliminates the need for sequential ion channel activation along the axon, allowing myelinated fibers to achieve transmission speeds up to 50 times faster than their unmyelinated counterparts (Paez and Lyons, 2020; Sock and Wegner, 2021; Suminaite et al., 2019; Tiane et al., 2019; Yi et al., 2023). Recent research indicates that OLs can dynamically adjust myelin thickness and internodal length to meet the conduction requirements of specific neural circuits. Although myelination substantially increases the speed of action potential propagation, its precise functional impact is determined by specific structural parameters (Osso and Hughes, 2024). Myelin, the specialized membrane that envelops neuronal axons, is essential for maintaining axonal integrity and functionality (Kent and Miron, 2024). It provides metabolic support to axons and preserves their structural and functional homeostasis (Simons et al., 2024). The enhanced production and transport of lactate by myelin exert neuroprotective effects on axons. The myelin sheaths surrounding these axons form specialized conduits known as “myelin channels,” which facilitate the transport of lactate and other neurotrophic factors to axons, thereby supporting axonal structural maintenance and viability. Oligodendrocytes provide energy substrates, such as lactate, to axons through these myelin channels, meeting their high metabolic demands during neural activity (Ruskamo et al., 2022). Additionally, myelin acts as a physical barrier that shields axons from external neurotoxic substances, such as inflammatory cytokines and oxidative stress byproducts, thereby delaying axonal degeneration. The composition and structural integrity of myelin are crucial for its physiological functions. Myelin basic protein (MBP) plays a vital role in myelin compaction, which is essential for maintaining the insulating properties of myelin sheaths. The interaction between MBP and lipid membranes, particularly in the presence of cholesterol, is critical for the structural stability of myelin. Variations in cholesterol content influence MBP-lipid monolayer interactions, thereby affecting myelin membrane compaction and thermodynamic stability (Träger et al., 2020). Moreover, myelin exhibits heterogeneous distribution and thickness along axons, with significant variations across different neuronal populations. Recent studies have found that OLs in adult CNS can still dynamically adjust myelin thickness and participate in learning and memory. For example, experiments on mice have shown that myelination is associated with complex motor skills (McKenzie et al., 2014).

Myelination plays a crucial role in significantly enhancing the velocity of action potential propagation along axons (Figure 1). As an effective passive electrical insulator, myelin sheaths substantially increase conduction speed (Yamazaki et al., 2010). The conduction velocity of neurons is influenced by factors such as axonal diameter, myelin thickness, and internodal distance (Steadman et al., 2020). By reducing axonal membrane capacitance and resistance, myelin extends the electrotonic length constant of axons, decreases the likelihood of action potential propagation failure, and markedly enhances the efficiency of neural signal transmission (Nave, 2010). Moreover, myelin improves the fidelity of information transmission through its biophysical properties (Alcami and El Hady, 2019; Cohen et al., 2020) and by facilitating metabolic support from OLs to axons (Moore et al., 2020).

Aerobic glycolysis in OLs is a crucial energy source for axonal metabolism (López-Muguruza and Matute, 2023) (Figure 1). Research conducted by Hu et al. (2024) has elucidated that the Erythroblastic Leukemia Viral Oncogene Homolog (ErbB) signaling pathway plays a regulatory role in the expression of lactate dehydrogenase. This regulation influences the capacity for lactate shuttling from OLs to axons, which is essential for maintaining axonal conduction. Inhibition of the ErbB pathway results in working memory deficits in mice, indicating that cognitive impairments can occur due to metabolic dysfunction, even when myelin remains structurally intact. Lactate functions as both a critical energetic substrate and a metabolic signaling molecule within the brain and astrocytes, significantly contributing to energy transfer, storage, production, and utilization (Wu et al., 2023). In the context of CNS energy metabolism, monocarboxylates such as lactate and pyruvate are released into the perineuronal microenvironment through glia-specific MCT1 transporters. These substrates are subsequently taken up by neurons via neuron-expressed Monocarboxylate Transporter 2 (MCT2) transporters, thereby providing essential energetic substrates for neural activity. Neurotransmitter signaling and neurotrophic factors exert functional effects on oligodendrocyte lineage cells (Mount and Monje, 2017). Neurotransmitter signaling and neurotrophic factors have significant functional impacts on cells within the oligodendrocyte lineage. Oligodendrocyte precursor cells (OPCs) perceive neuronal activity via glutamate receptors, such as AMPA and NMDA receptors, which subsequently influence myelination and play a role in the regulation of learning and memory (Gallo et al., 1996; Wake et al., 2011). Concurrently, OPCs express GABA receptors, allowing the inhibitory neurotransmitter GABA to modulate their differentiation rate, alter myelination processes, and affect cognitive flexibility (Zonouzi et al., 2015). The release of molecules like glutamine and BDNF plays a crucial role in regulating neurotransmitter release and metabolism, thereby influencing cognitive abilities. Research has demonstrated that the knockout of BDNF in the mouse hippocampus results in reduced myelin thickness and diminished performance in spatial memory tasks (Du et al., 2011).

Schizophrenia is a complex neurodevelopmental disorder involving the interplay of genetic, environmental, and neurobiological factors, characterized by significant disturbances in thinking, perception, emotion, behavior, and social functioning. Recent studies have revealed that oligodendrocyte (OL) dysfunction and myelination abnormalities play a critical role in the pathological mechanisms of schizophrenia, potentially affecting neural signal transmission, synaptic plasticity, and brain network integration.

Oligodendrocyte and myelination abnormalities in schizophrenia may impair cognitive and emotional functions through mechanisms such as white matter connectivity deficits, impaired synaptic plasticity, and neuroinflammation. Research indicates that oligodendrocyte abnormalities in schizophrenia patients may be associated with reduced oligodendrocyte density, such as a significant decrease in OL numbers in key brain regions like the PFC, hippocampus, and corpus callosum, along with downregulated OLIG2 expression. Concurrently, schizophrenia exhibits abnormal expression of myelin-related genes, with microarray analyses showing reduced expression of genes such as myelin basic protein (MBP) and PLP in the brains of schizophrenia patients (Tkachev et al., 2003), as well as decreased levels of CNP (2’,3’-cyclic nucleotide 3’-phosphodiesterase, an OL marker) protein (Flynn et al., 2003).

Neuroimaging studies suggest that white matter abnormalities in schizophrenia patients are closely linked to impaired oligodendrocyte function. Research has demonstrated that the ERBB4/NRG1 signaling pathway is frequently mutated in schizophrenia patients, affecting oligodendrocyte differentiation and thereby compromising white matter integrity, ultimately leading to cognitive dysfunction (Hu et al., 2024). Studies have found that disruption of ErbB signaling impairs oligodendrocyte myelination and aerobic glycolysis, resulting in working memory deficits. The loss of ErbB signaling in OLs reduces axonal myelin sheath thickness and slows conduction velocity (Dong and Zhen, 2015). Specific inhibition of the ErbB signaling pathway in OPCs leads to structural defects in myelin, directly associated with working memory impairment (Hu et al., 2024). When ErbB signaling is blocked in OLs in vivo, changes in oligodendrocyte quantity and morphology are accompanied by reduced myelin thickness, slower CNS axonal conduction velocity, and behavioral alterations (Roy et al., 2007).

Mechanistically, ErbB inhibition attenuates K-Ras activity, leading to decreased expression of lactate dehydrogenase A (LDHA), which is essential for promoting aerobic glycolysis in mature OLs. Supplementation with L-lactate can restore axonal conduction and working memory capacity impaired by ErbB inhibition in mature OLs (Hu et al., 2024). These findings suggest that abnormal myelination may contribute to the cognitive dysfunction observed in schizophrenia. Furthermore, oligodendrocyte dysfunction has been implicated in both schizophrenia and depression. Research indicates that antipsychotic medications, such as haloperidol, olanzapine, and quetiapine can promote the differentiation of OPCs into mature OLs by modulating transcription factors Olig1 and Olig2 (Fang et al., 2013). This process promotes oligodendrocyte development, improves myelin integrity (Zhang et al., 2012), and alleviates cognitive dysfunction (Gingele and Stangel, 2020).

In Alzheimer’s disease, oligodendrocyte function is compromised by various factors, including aging, aluminum toxicity, small vessel disease with associated white matter injury, and amyloid-beta (Aβ) pathology. Importantly, alterations in myelination patterns and oligodendrocyte function are evident in the early stages of AD, preceding the formation of detectable Aβ plaques and tau pathology. Research indicates a significant reduction in myelin density within brain regions affected by AD, such as the hippocampus and anterior cingulate cortex, with the degree of myelination loss positively correlating with the severity of cognitive impairment. Myelin pathology may exacerbate neurodegenerative processes by disrupting axonal metabolic support and compromising neural circuit stability. Oligodendrocyte dysfunction becomes apparent in the early stages of AD, primarily manifesting as myelin loss and dysregulation of lipid metabolism. Notably, simultaneous processes of myelination breakdown and repair occur throughout the progression of AD. Studies conducted on AD model mice demonstrate that although there is an accelerated compensatory myelination response, it remains insufficient to counteract myelin degradation, suggesting that cognitive decline is associated with the dynamics of myelin turnover (Chen et al., 2021). Cutting-edge single-nucleus RNA sequencing of postmortem brain tissue identifies IL-12 signaling as a driver of AD pathogenesis, unveiling potential therapeutic targets.

Multiple sclerosis constitutes a distinct category of CNS disorders, characterized by progressive myelin degradation and persistent neuroinflammatory responses. The process of demyelination in MS is directly linked to cognitive decline. Research indicates that the primary impediment to remyelination in chronic MS lesions is impaired oligodendrocyte maturation. The terminal differentiation of OLs is meticulously regulated by both cell-intrinsic mechanisms and microenvironmental cues. Dysfunction in the differentiation of OPCs undermines remyelination capacity, resulting in axonal damage and neuronal loss, which ultimately leads to irreversible neurological deficits—a hallmark of progressive MS. Meanwhile, studies have also found that alterations in glucose metabolism affect the energy supply required for oligodendrocyte function and myelin synthesis (López-Muguruza and Matute, 2023). During development, thyroid hormone (TH) promotes myelination by enhancing oligodendrocyte differentiation. Both TH and sobetirome stimulate remyelination in demyelination models, and long-term treatment significantly improves remyelination repair and motor recovery (Hartley et al., 2019).

Myelin repair can be facilitated by modulating the differentiation of OPCs or by enhancing the metabolic functions of OLs. Research indicates that neuronal activity can stimulate the proliferation and differentiation of OPCs, as well as influence the spatial distribution of newly formed myelin sheaths. Animal studies have demonstrated that exercise training can increase the turnover rate of OLs during remyelination and improve the efficiency of myelin regeneration (Bacmeister et al., 2020). Clinical investigations utilizing magnetic resonance imaging (MRI) have revealed that structural changes in white matter, including myelin production or remodeling, are linked to specific types of learning, particularly motor skills such as playing musical instruments or juggling (Bergles and Richardson, 2015). Furthermore, in vitro studies have shown that electrical stimulation of neuronal activity can enhance the proliferation and myelin formation of OPCs (Ronzano et al., 2020) (Figure 2).